Medicinal Chemistry Perspectives on Molecular Targets and Targeted Therapeutic Strategies in Breast Cancer

Breast cancer is one of the major causes of morbidity and mortality in cancer among women in the global society. The condition is highly heterogeneous and shows significant variation in molecular subtypes, clinical behaviour, and response to treatment. Despite significant progress in early diagnosis and the development of targeted treatment approaches, therapeutic resistance and tumour recurrence remain obstacles to long-term disease control. In this review, the authors provide a detailed discussion of new therapeutic targets in breast cancer and the most important molecular pathways associated with resistance to existing therapies. Hormone receptor-positive, HER2- positive, and triple-negative breast cancer are major subtypes of breast cancer that have different molecular characteristics and therapeutic vulnerabilities. The estrogen receptor alpha remains a key part of endocrine therapy in hormone receptor-positive breast cancer, but acquired resistance often occurs as a result of ESR1 gene mutations and receptor conformational changes. Monoclonal antibodies, antibody drug conjugates, and tyrosine kinase inhibitors, which are HER2-targeted therapies, play a significant role in improving outcomes in HER2-positive tumours, but intrinsic and adaptive resistance remain significant clinical challenges. Immunity checkpoint inhibitors such as atezolizumab are increasingly used in the treatment of triple-negative breast cancer, a cancer type that does not have known hormonal and HER2 targets, especially in tumours that express PD L1. The dysregulation of several important signalling pathways, including PI3K, AKT, mTOR, and CDK4/6, has been observed in most breast cancer subtypes and offers valuable targets for therapeutic intervention, as exemplified recently by the approval of agents like alpelisib and inavolisib. Moreover, androgen receptor signalling, particularly on certain subsets of triple-negative breast cancer, has become another potentially fruitful therapeutic target. The tumour microenvironment is a major component of cancer stem cells, immune cells, and stromal elements that are important for tumour progression and treatment resistance. Crosstalk between cancer stem cells and the tumour microenvironment, mediated by signalling pathways including Wnt, Notch, and Hedgehog, is a promising area of research for developing new therapeutic approaches. Further insight into these molecular targets and resistance pathways is key to developing an individualised, sustainable treatment regimen for breast cancer.